Many lines of evidence point towards the SIR having a vital role in pancreatic and liver damage. The signals which promote resolution of the SIR are poorly understood. Lactate and beta- hydroxybutyrate are produced at sites of inflammation and signal through specific cell curface receptors GPR81 and GPR109a, respectively. Our preliminary data demonstrate that in acetaminophen or LPS/galactosamine induced acute liver injury and in caerulein-induced acute pancreatitis: i. supplementation with lactate or beta-hydroxybutyrate decreases inflammation and tissue injury in the liver and pancreas and decreases TLR driven pro- inflammatory responses in macrophages in vitro, ii. in vivo knockdown of GPR81 or GPR109a markedly enhances liver injury, reduces induction of the cytoprotectant hmox1, and promotes mortality in LPS/galactosamine induced hepatitis, iii. GPR81 and GPR109a expression is predominantly in the macrophage compartment in the liver, and iv. lactate and beta-hydroxybutyrate require the GPR interacting protein ARRB2 for suppression of TLR4 driven pro-inflammatory responses in macrophages. It is known that ARRB2 signaling suppresses NF-B dependent pro-inflammatory signaling downstream of TLR receptors. It is also known that the GPR109a agonist niacin induces hmox1 through an NFE2 transcription factor dependent pathway. HMOX1 is known to promote polarization of macrophage immune phenotype towards the M2 alternatively active state and away from the M1 classical pro- inflammatory state. We hypothesize that GPR81 and GPR109a receptors and their ligands limit innate immune mediated inflammation through beta-arrestin 2 (ARRB2) pathways and NFE2-dependent heme-oxygenase 1 (HMOX1) pathways. AIM 1: Identify the contribution of ARRB2 and NFE2 signaling to GPR81 and GPR109a mediated modulation of the sterile inflammatory response through use of knockout mice for arrb2 and nfe2 and study of isolated macrophages and in vivo models of acute pancreatitis and acute liver injury. AIM 2: Determine synergy between GPR81 and GPR109a signaling in inducing hmox1 and suppressing NF-B dependent pro-inflammatory responses to TLR4 and TLR9 ligands in isolated macrophages, in vivo with LPS treatment, and in vivo in LPS/cearulein pancreatitis. The proposed work will identify a detailed cellular and molecular mechanism for GPR81 and GPR109a mediated regulation of the sterile inflammatory response.